Knorr pyrrole synthesis conventional

A modified Knorr pyrrole synthesis was key to a practical synthesis of the potent 5-opioid agonist SB-342219 by GSK. SB-342219 is a selective 5-opioid agonist undergoing preclinical evaluation for the potential treatment of neuropathetic pain. The medicinal chemistry route used the conventional Knorr pyrrole synthesis. Condensation of the ketone with a-aminoketone, which was generated in situ by reduction of the requisite phenylhydrazone using zinc, gave the desired pyrrole in 63% yield. 

The conventional Knorr pyrrole synthesis delivered SB-342219 on a small scale for medicinal chemistry. Nonetheless, use of metallic zinc... 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

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